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Boston Medical Center is the primary teaching affiliate
of the Boston University School of Medicine.
Overview of Hereditary Transthyretin
Amyloidosis (hATTR)
Frederick L. Ruberg, MD
Amyloidosis Center, Boston University School of Medicine
Section of Cardiovascular Medicine and Department of Radiology
Boston Medical Center
Boston, MA
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DISCLOSURES
• Grant support – NIH (NHLBI), Eidos
Therapeutics, Akcea Therapeutics (pending),
Pfizer
• Consulting – Pfizer
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GENETICS: BASIC BIOLOGY –
DNA STRUCTURE
https://microbenotes.com/dna-structure-properties-types-and-functions/
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GENETICS: BASIC BIOLOGY –
AMINO ACID CODES
http://biology.kenyon.edu/courses/biol114/Chap05/Chapter05.html
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GENETICS: BASIC BIOLOGY – DNA, RNA,
AND PROTEINS
Clancy and Brown, Nature Education 2008
DNA
mRNA
Protein
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https://www.genome.gov/sites/default/files/tg/en/illustration/amino_acids.jpg
GENETICS: BASIC BIOLOGY – PROTEIN
STRUCTURE
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GENETICS: BASIC BIOLOGY – SINGLE
NUCLEOTIDE POLYMORPHISMS (SNP)
Normal Protein
Abnormal Protein
Common diseases caused by SNPs – sickle cell anemia, cystic fibrosis
Missense mutation
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https://www.genome.gov/sites/default/files/tg/en/illustration/amino_acids.jpg
GENETICS: BASIC BIOLOGY – PROTEIN
STRUCTURE WITH SNP
Gln
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GENETICS: BASIC BIOLOGY –
DNA ORGANIZED INTO CHROMOSOMES
https://www.biology.iupui.edu/biocourses/N100/2k2humancsomaldisorders.html
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GENETICS: BASIC BIOLOGY –
AUTOSOMAL DOMINANCE
https://baguioejournal.wordpress.com
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HEREDITARY ATTR (hATTR) AMYLOIDOSIS
• Autosomal dominant (50% chance of passage to
offspring)
– AKA ATTRv (variant) or ATTm (mutant)
• Missense SNP – change in amino acid of TTR
protein causing misfolding of the protein and
amyloid deposits
• Present since birth, amyloidosis develops with age
• Naming – Normal amino acid-position in protein-
Substituted amino acid
• Example Val122Val --> Val122Ile
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JUST TO MAKE IT EXTRA CONFUSING…
• Protein mutation locations now reported with 20
amino acid signal peptide at start
• So Val122Ile or V122I is now reported at pV142I
• And Val30Met or V30M is now reported at
pV50M
• SO – Val122Ile or V122I = pVal142Ile or V142I
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hTTR IS CAUSED BY SNP RESULTING IN
AMYLOIDOSIS OF DIFFERENT ORGAN SYSTEMS
• Cardiac - Congestive heart failure, arrhythmia, conduction disease
(previously called FAC)
• Neurological - peripheral sensory and autonomic neuropathy
• (previously called FAP)
Maurer, Circulation: Heart Failure 2019
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TTR STRUCTURE AND AMYLOID
FIBRIL FORMATION
Bulawa et al. PNAS 2012 Bulawa et al. PNAS 2012
Ruberg, J Am Coll Cardiol, 2019
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SIGNS AND SYMPTOMS OF hATTR
https://hattramyloidosis.co.uk/en-gb/symptoms
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HOW COMMON IS hATTR AMYLOIDOSIS?
• Estimated world-wide prevalence of 50,000
people (predominantly with neuropathy)
• BUT V122I shown convincingly in about 3.5%
US African Americans = 1,500,000 people with
genotype
– 150,000 are over age 65 y and at highest risk
for hATTR
• Ongoing subject of active study (SCAN-MP, PI’s
Maurer/Ruberg, NHLBI)
Gertz, Am J Managed Care 2017
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ATTR AMYLOIDOSIS IS UNRECOGNIZED (EVEN
AT BOSTON UNIVERSITY CARDIOLOGY CLINIC)
101 African Americans with
HF, age > 60y, and wall thickness >/=
12 mm
6.7% males were V122I gene
positive 60% penetrance
Arvanitis, Amyloid 2017
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hATTR ACROSS CONTINENTAL
EUROPE – COUNTRY OF ORIGIN
Damy, EHJ 2019
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DETERMINATION OF GENOTYPE IS
CRITICAL TO TREATMENT
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ANYONE CAN KNOW THEIR TTR
GENOTYPE
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ANYONE CAN KNOW THEIR TTR
GENOTYPE – 23&ME
https://www.23andme.com/test-info/
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UNANSWERED QUESTION #1
• Genotype carriers (phenotype negative)
– When to initiate therapy?
• Prior to development of symptoms
– What to prescribe?
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UNANSWERED QUESTION #2 • When to recommend testing of offspring or
siblings of affected patients?
– Above an age threshold?
– At the predicted age of disease onset
(PADO) or some defined time prior?
• Mutation, sex, and family dependent
Obici, Cur Opin Neurol 2016
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Maurer, Circulation: Heart Failure 2019
Also to consider – prealbumin (TTR) concentration
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Dorbala, J Nuc Med and J Card Fail, 2019
THE FIRST GUIDELINES IN AMYLOIDOSIS!
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ORTHOPEDIC MANIFESTATIONS –
EARLIEST CLUES? 98 patients 10 new cases
and 2 with hATTR
Other clinical clues:
• Bilateral carpal tunnel
• Spinal Stenosis
• Spontaneous biceps
tendon rupture
Sperry, Hanna JACC 2018
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CONCLUSIONS
• hATTR results from a single base pair change in the TTR
gene, that causes a change in the TTR protein resulting
in misfolding and amyloid fibril formation
• hATTR is passed down to children in an autosomal
dominant manner (50% chance of passage)
• The type of mutation determines the predicted symptoms
and organ systems that are affected
• Determination of genotype is critical to selecting
treatment
• We must move toward early identification to give
treatments the best chance to work
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AMYLOIDOSIS CENTER
BOSTON UNIVERSITY/ BOSTON MEDICAL CENTER
http://www.bu.edu/amyloid/
@Amyloidosis_BU